CA2460935A1 - An improved preparation of atorvastatin - Google Patents

An improved preparation of atorvastatin Download PDF

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Publication number
CA2460935A1
CA2460935A1 CA002460935A CA2460935A CA2460935A1 CA 2460935 A1 CA2460935 A1 CA 2460935A1 CA 002460935 A CA002460935 A CA 002460935A CA 2460935 A CA2460935 A CA 2460935A CA 2460935 A1 CA2460935 A1 CA 2460935A1
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CA
Canada
Prior art keywords
hydroxy
pyrrol
phenylamino
methylethyl
fluorophenyl
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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CA002460935A
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French (fr)
Other versions
CA2460935C (en
Inventor
Bhaskar Reddy Guntoori
Daqing Che
Fan Wang
Yajun Zhao
K.S. Keshava Murthy
Stephen E. Horne
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Apotex Pharmachem Inc
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Apotex Pharmachem Inc
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Application filed by Apotex Pharmachem Inc filed Critical Apotex Pharmachem Inc
Priority to CA2460935A priority Critical patent/CA2460935C/en
Priority to US10/800,741 priority patent/US7193090B2/en
Priority to AU2005221733A priority patent/AU2005221733B2/en
Priority to EP05714608A priority patent/EP1725527A4/en
Priority to JP2007503158A priority patent/JP2007529429A/en
Priority to PCT/CA2005/000368 priority patent/WO2005087723A1/en
Publication of CA2460935A1 publication Critical patent/CA2460935A1/en
Application granted granted Critical
Publication of CA2460935C publication Critical patent/CA2460935C/en
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Expired - Fee Related legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A process for preparing (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester comprising:
(a) reduction of 5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-oxo-1-pentanoic acid, (R)-2-hydroxy-1,2,2-triphenylethyl ester;
(b) hydrolysis of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxy-1-pentanoic acid, (R)-2-hydroxy-1,2,2-triphenylethyl ester using an alkali base in a solvent to form the acid;
(c) alkylation of the acid forming (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester.

Claims (22)

1. A process for preparing (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester comprising:
(a) reduction of 5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-oxo-1-pentanoic acid, (R)-2-hydroxy-1,2,2-triphenylethyl ester;
(b) hydrolysis of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxy-1-pentanoic acid, (R)-2-hydroxy-1,2,2-triphenylethyl ester using an alkali base in a solvent to form the acid;
(c) alkylation of the acid forming (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester.
2. A process for the preparation of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester according to claim 1 using an alkali metal hydroxide as the alkali base.
3. A process for the preparation of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester according to claim 1 using lithium hydroxide, sodium hydroxide or potassium hydroxide.
4. A process for the preparation of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester according to claim 1 using sodium hydroxide.
5. A process for the preparation of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester according to claim 1 using potassium hydroxide.
6. A process for the preparation of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester according to claim 1 where the solvent is methanol or water or a mixture thereof.
7. A process for the preparation of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester according to claim 1 using from about 1 to about 10 equivalents of an alkali metal base.
8. A process for the preparation of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester according to claim 1 using from about 2 to about 8 equivalents of an alkali metal base.
9. A process for the preparation of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, tert-butylester according to claim 1 using about 5 equivalents of an alkali metal base.
10. (R)-5-[2-(4-Fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxy-I-pentanoic acid.
11. Preparation of Atorvastatin or pharmaceutically acceptable salts thereof using the process of any one of claims 1 to 9.
12. A process according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 11 where the chiral auxiliary (R)-1,1,2-triphenyl-1,2-ethanediol is recovered.
13. A process according to claim 12 where the chiral auxiliary (R)-1,1,2-triphenyl-1,2-ethanediol is recovered in optically enriched form.
14. A process according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12 or 13 where the intermediate (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxy-1-pentanoic acid is not isolated.
15. A process according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13 or 14 where (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid tert-butylester is prepared using mono-tert-butyl malonate in the presence of a base.
16. A process according to claim 15 where the base is a metal alkoxide.
17. A process according to claim 16 where the base is magnesium ethoxide.
18. A process for the preparation of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxy-1-pentanoic acid, methylester from (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxy-1-pentanoic acid.
19. A process for the preparation of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxy-1-pentanoic acid comprising hydrolysis of (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxy-1-pentanoic acid, (R)-2-hydroxy-1,2,2-triphenylethyl ester.
20. The process of claim 19 wherein said hydrolysis is carried out using a base.
21. The process of any one of claims 19 to 20 wherein said process is carried out in the presence of a solvent.
22. 5-[2-(4-Fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-pyrrol-1-yl]-3-oxo-1-pentanoic acid, (R)-2-hydroxy-1,2,2-triphenylethyl ester.
CA2460935A 2004-03-15 2004-03-15 An improved preparation of atorvastatin Expired - Fee Related CA2460935C (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA2460935A CA2460935C (en) 2004-03-15 2004-03-15 An improved preparation of atorvastatin
US10/800,741 US7193090B2 (en) 2004-03-15 2004-03-16 Preparation of atorvastatin
AU2005221733A AU2005221733B2 (en) 2004-03-15 2005-03-11 An improved preparation of Atorvastatin
EP05714608A EP1725527A4 (en) 2004-03-15 2005-03-11 An improved preparation of atorvastatin
JP2007503158A JP2007529429A (en) 2004-03-15 2005-03-11 Improved production of atorvastatin
PCT/CA2005/000368 WO2005087723A1 (en) 2004-03-15 2005-03-11 An improved preparation of atorvastatin

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CA2460935A CA2460935C (en) 2004-03-15 2004-03-15 An improved preparation of atorvastatin

Publications (2)

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CA2460935A1 true CA2460935A1 (en) 2005-09-15
CA2460935C CA2460935C (en) 2010-05-18

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CA2460935A Expired - Fee Related CA2460935C (en) 2004-03-15 2004-03-15 An improved preparation of atorvastatin

Country Status (6)

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US (1) US7193090B2 (en)
EP (1) EP1725527A4 (en)
JP (1) JP2007529429A (en)
AU (1) AU2005221733B2 (en)
CA (1) CA2460935C (en)
WO (1) WO2005087723A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1853559A4 (en) * 2005-02-28 2010-01-13 Apotex Pharmachem Inc An improved process for the preparation of atorvastatin and intermediates

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060009506A1 (en) * 2004-07-09 2006-01-12 Odyssey Thera, Inc. Drugs for the treatment of neoplastic disorders
WO2011028309A1 (en) 2009-09-04 2011-03-10 University Of Toledo PROCESSES FOR PRODUCING OPTICALLY PURE β-LACTONES FROM ALDEHYDES AND COMPOSITIONS PRODUCED THEREBY

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI94339C (en) * 1989-07-21 1995-08-25 Warner Lambert Co Process for the preparation of pharmaceutically acceptable [R- (R *, R *)] - 2- (4-fluorophenyl) -, - dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H- for the preparation of pyrrole-1-heptanoic acid and its pharmaceutically acceptable salts

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1853559A4 (en) * 2005-02-28 2010-01-13 Apotex Pharmachem Inc An improved process for the preparation of atorvastatin and intermediates

Also Published As

Publication number Publication date
EP1725527A4 (en) 2010-12-01
AU2005221733A1 (en) 2005-09-22
WO2005087723A1 (en) 2005-09-22
US7193090B2 (en) 2007-03-20
AU2005221733B2 (en) 2011-03-17
JP2007529429A (en) 2007-10-25
US20050203302A1 (en) 2005-09-15
CA2460935C (en) 2010-05-18
EP1725527A1 (en) 2006-11-29

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